19-Hydroxy-19-methyl-13,14-dihydro-PG2 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-13,14-dihydro-PG 2  compounds, methods for their preparation and pharmacological use for the induction of prostaglandin-like effect.

DESCRIPTION Cross Reference to Related Applications

The present application is a division of Ser. No. 025,878, filed 2 Apr. 1979 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandin analogs. Particularly, these compounds are analogs of the prostaglandins wherein the C-19 position is substituted by hydroxy, i.e., 19-hydroxy-19-methyl-PG compounds. Most particularly, the present invention relates to novel 19-hydroxy-19-methyl-13,14-dihydro-PG₂ compounds, a disclosure of the preparation and use of which is incorporated here by reference from U.S. Ser. No. 025,899, filed 2 Apr. 1979 now U.S. Pat. No. 4,228,104.

PRIOR ART

Prostaglandin analogs exhibiting hydroxylation in the 19-position are known in the art. See, for example, U.S. Pat. No. 4,127,612, Sih, J. C., Prostaglandins 13:831 (1977) and U.S. Pat. Nos. 3,657,316, 3,878,046, and 3,922,297. See also the additional references cited in U.S. Ser. No. 025,878.

SUMMARY OF THE INVENTION

The present invention particularly provides: a compound of the formula ##STR1## wherein D is (1) cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or

(2) cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --,

wherein g is zero, one, two, or three;

wherein Q is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl;

wherein R₆ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive,

(g) --(p--Ph)--CO--CH₃,

(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃,

(i) --(p--Ph)--NH--CO--(p--Ph),

(j) --(p--Ph)--NH--CO--CH₃,

(k) --(p--Ph)--NH--CO--NH₂,

(l) --(p--Ph)--CH═N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₂₈,

wherein (p--Ph) is para-phenyl or inter-para-phenylene,

wherein R₂₈ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation;

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro;

wherein W is oxo, methylene, α-OH:β-H, or α-H:β-OH; and

wherein X is --CH₂ CH₂ --.

With regard to the divalent the substituents described above (e.g., Q) these divalent radicals are defined as α-R_(i) :β-R_(j), wherein R_(i) represents the substituent of the divalent moiety in the alpha configuration with respect to the ring and R_(j) represents the substituent of the divalent moiety in the beta configuration with respect to the plane of the ring. Accordingly, when Q is defined as a-OH:β-R₅, the hydroxy of the Q moiety is in the alpha configuration, i.e., as in the natural prostaglandin, and the R₅ substituent is in the beta configuration.

Specific embodiments of the present invention include:

19-hydroxy-19-methyl-13,14-dihydro-PGF₂ α.

The compounds of the present invention are particularly useful for inducing prostaglandin-like biological effects, as is described in U.S. Ser. No. 025,878. Uses of compounds in accordance with the present invention include, therefore, anti-asthmatic indications. 

I claim:
 1. A compound of the formula ##STR2## wherein D is (1) cis--CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or(2) cis--CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, wherein g is zero, one, two, or three; wherein Q is α-OH:β-R₅ or α-R₅ :β-OH, wherein R₅ is hydrogen or methyl; wherein R₆ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, (g) --(p--Ph)--CO--CH₃, (h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH.sub., (i) --(p--Ph)--NH--CO--(p--Ph), (j) --(p--Ph)--NH--CO--CH₃, (k) --(p--Ph)--NH--CO--NH₂, (l) --(p--Ph)--CH═N--NH--CO--NH₂, (m) β-naphthyl, (n) --CH₂ --CO--R₂₈, wherein (p--Ph) is para-phenyl or inter-para-phenylene, wherein R₂₈ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or(o) a pharmacologically acceptable cation; wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl; wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein W is oxo, methylene, α-OH:β:H, or α-H:β-OH; and wherein X is --CH₂ CH₂ --.
 2. 19-hydroxy-19-methyl-13,14-dihydro-PGF₂ α, a compound according to claim
 1. 